The present invention, in some embodiments thereof, relates to methods and pharmaceutical compositions for treating pathologies characterized by hyperproliferative keratinocytes.
Psoriasis is a chronic inflammatory skin disease affecting approximately 2-5% of the general population worldwide. The etiology of psoriasis is multifactorial and it is thought to result from the interactions between environmental and genetic factors. Typical histopathological features in psoriasis include both epidermal (hyperparakeratosis) and immunological (neutrophil microabscesses and dermal mononuclear infiltrate and blood vessel proliferation) abnormalities. Psoriasis is characterized by increased proliferation, decreased apoptosis and abnormal differentiation of keratinocytes and can be often associated with other diseases or conditions such as arthritis, cardiovascular disease, chronic obstructive pulmonary disease (COPD), diabetes and the like.
Current treatments of psoriasis include the topical administration of coal tar, vitamin D derivatives, retinoids, and calcineurin inhibitors; phototherapy using UVB, NB-UVB, and/or laser; combined systemic and phototherapy (e.g., oral administration of psoralen followed by exposure to UVA); systemic administration of Cyclosporine, methotrexate, retinoids and the like; and administration of biological agents such as Alafacept, infliximab, etanercept and ustekinumab.
The etiology of psoriasis is not clear. Various candidate genes were found to be associated with genetic predisposition to develop the disease (Griffiths and Barker, 2007; Lowes et al., 2007; Nair et al., 2009; Nair et al., 2006; Yang et al., 2008; Zenz et al., 2008; Zenz and Wagner, 2006; Zhang et al., 2009), demonstrating the involvement of both immunological dysfunction and epidermal defects in the pathogenesis of the disease.
Various animal models have been used to mimic the phenotype of psoriasis. For example, inducible epidermal deletion of Jun proteins was found to cause psoriasis-like skin disease and arthritis (Zenz et al., 2005). In addition, loss of serum response factor (SRF) in keratinocytes was found to result in hyperproliferative skin disease in mice (Koegel et al., 2009). Furthermore, Shon et al. [Exp Dermatol. 2008 August; 17(8):703-12] reviewed animal models of the disease and found that these models reflect the dual etiology of psoriasis.
Genomic-scale analysis of psoriatic skin in patients before and after phototherapy revealed a marked up-regulation of IGFBP7, encoding the insulin-like growth factor binding protein 7 (IGFBP7) (Hochberg M., Zeligson S., et al., 2007).
IGFBP7 belongs to the IGFBP superfamily, a large group of secreted proteins, which share a common N-terminal cysteine rich domain. A total of 16 family members have been identified, 6 of which bind IGFs with a high affinity (IGFBP1-6), the other 10 members binding insulin growth factors (IGFs) with a low affinity. IGFBP7 (also called IGFBP-rP1 or MAC25) binds IGFs with a low affinity, but recognizes insulin with a high affinity, and thereby modifies its metabolism, distribution, and ability to bind to the insulin receptor. IGFBP7 has IGF/insulin-independent actions. For example, IGFBP7 contains a “follistatin module”, which enables its binding to activin, a member of the TGF-β superfamily of growth factors, that regulates normal mammary cell function, gonadal functions and follicle stimulatory hormone (FSH) release. IGFBP7 has been shown to regulate cell proliferation, cell adhesion, cellular senescence and angiogenesis in different cancer cell lines (Akaogi et al., 1996; Burger et al., 2005; Ruan et al., 2007; Sato et al., 2007; Wilson et al., 2002). More recently, IGFBP7 has been shown to mediate senescence and apoptosis in melanocytes and to suppress melanoma growth in vivo (Wajapeyee et al., 2008).
IGFBP7 is expressed in a ubiquitous fashion and can be found in its secreted form in all human biological fluids such as serum, urine and amniotic fluid (Degeorges et al., 2000; Lopez-Bermejo et al., 2003). IGFBP7 is inactivated by proteolytic processing; in addition, hypermethylation has been reported to also affect its expression in neoplastic tissues. IGFBP7 is induced by TGF-β, glucocorticoids and retinoic acid. IGFBP7 has been found to be one of several keratinocyte-specific genes differentially expressed in keratinocytes compared with nonkeratinocyte cell types (Gazel et al., 2003).
U.S. Patent Application 20090035312 teaches methods of identifying specific target molecules for design of anti-angiogenic and vascular targeting approaches and inhibition of angiogenesis in vitro and in vivo using antibodies targeting of vimentin, CD59, HMGB1 and IGFBP7.
Additional background art include Candille et al., Science 2007; Lande et al., Nature 2008; Chamorro et al., J. Invest. Dermatolo. 2009; Duncan et al., J. Invest. Dermatol. 1994; Kruger-Krasagakis et al., Br. J. Dermatol. 2006; Wrone-Smith et al., Am. J. Pathol. 1997; Komine et al., J. Invest Dermatol. 2007; Rahmoun et al, J Invest Dermatol, 2009; Krueger and Bowcock, 2005; McKay and Leigh, 1995; Bernerd et al., 1992; Bovenschen et al., 2005; Vissers et al., 2008; Haider et al., 2006; Bowen et al., 2004; Gunduz et al., 2006; Yang et al., 2009; Laporte et al., 2000; Raj et al., 2006; Yamanaka et al., 1997; Genua et al., 2009; Neely et al., 1991; Sadagurski et al., 2007; Wertheimer et al., 2001; Wertheimer et al., 2000; Nickoloff et al., 2006.